The prohibitin family and their function in myelination and axonal health

抽象的。 髓鞘是神经冲动传导和保护轴突所必需的。受损 髓磷脂的形成或破坏引起一系列使人衰弱的疾病。疾病 外周髓鞘是最常见的神经肌肉疾病之一， 严重残疾。外周髓磷脂- 形成雪旺细胞分化和髓鞘，它们如何保持健康的髓鞘 鞘以及它们如何支持轴突只是部分了解。使用创新的 为了研究细胞间的相互作用，我们最近发现了一个新的分子家族， 在体内的雪旺细胞中，与轴突相互作用、髓鞘形成和 维持健康的髓鞘和轴突。小鼠雪旺氏细胞中白藜芦醇苷的缺失导致 髓鞘形成障碍、脱髓鞘和轴突变性。抑制素是保守的 在线粒体、质膜和细胞核中发现的跨膜蛋白。他们 作为信号传导衔接子和分子伴侣，它们参与粘附，信号传导， 和衰老。我们建议使用最先进和创新的组合 体内和体外技术来测试许旺细胞中的抑制素-2是 在发育早期与轴突相互作用的质膜信号复合物的一部分， 而线粒体中的prohibitin-1/prohibitin-2复合物维持髓鞘和轴突 完整我们将确定bisbitins相互作用，并发现bisbitins如何调节 衰老、蛋白质稳态和线粒体功能。这些数据很可能 以确定髓鞘形成和轴突保护的新功能，并可能揭示 新的分子机制是重要的轴神经胶质细胞的相互作用，在外周 神经病

Abstract. Myelin is required for conduction of nerve impulses and to protect axons. Impaired formation or destruction of myelin causes a series of debilitating diseases. Diseases of peripheral myelin are among the most common neuromuscular disorders and cause significant disability. The fundamental mechanisms that underlie how peripheral myelin- forming Schwann cells differentiate and myelinate, how they maintain a healthy myelin sheath and how they support axons are only partially understood. Using an innovative system to study cell-cell interactions we recently identified a new family of molecules, the prohibitins, which are required in Schwann cells in vivo to interact with axons, myelinate and maintain healthy myelin and axons. Deletion of prohibitins in Schwann cells in mice causes dys-myelination, de-myelination and axonal degeneration. Prohibitins are conserved transmembrane proteins found in mitochondria, plasmamembranes and nuclei. They function as signaling adaptors and chaperones and they are involved in adhesion, signaling, and senescence. We propose to use a combination of state-of-the art and innovative techniques in vivo and in vitro to test the hypotheses that prohibitin-2 in Schwann cells is part of a plasma membrane signaling complex that interact with axons early in development, while a prohibitin-1/prohibitin-2 complex in the mitochondria maintains myelin and axon integrity. We will identify prohibitins interactors and discover how prohibitins regulate senescence, proteostasis and mitochondria function in Schwann cells. These data are likely to define the novel function of prohibitins in myelination and axon protection, and may reveal new molecular mechanisms that are important for axo-glial interactions during peripheral neuropathies.